A LiCl-mediated Br/Mg exchange reaction for the preparation of functionalized aryl- and heteroarylmagnesium compounds from organic bromides

Article abstract of DOI:10.1002/anie.200454084

A wide range of aryl and heteroaryl bromides, which are usually sluggish in exchange reactions, are readily converted into the corresponding Grignard reagents by means of a Br/Mg exchange reaction triggered by iPrMgCl·LiCl (see scheme). These Grignard intermediates react with electrophiles in good yields.

Full text of DOI:10.1002/anie.200454084

Angewandte
Chemie
Grignard Reactions
A LiCl-Mediated Br/Mg Exchange Reaction for
the Preparation of Functionalized Aryl- and
Heteroarylmagnesium Compounds from Organic
Bromides**
Arkady Krasovskiy and Paul Knochel*
Dedicated to Professor Friedrich Bickelhaupt
Polyfunctionalized organometallic reagents are ubiquitous
[
1]
intermediates in modern organic chemistry. One of the best
methods for preparing these reagents is the halogen–metal
[
1,2]
exchange reaction.
Whereas Br/Li exchange is fast and
occurs at low temperatures, the corresponding Br/Mg
[
3]
exchange is considerably slower, which limits its synthetic
application for several reasons: 1) The exchange requires
higher reaction temperatures and is therefore not compatible
with many functional groups; 2) The slow Br/Mg exchange
especially for electron-rich aromatic bromides is in competi-
tion with the elimination of HBr from the alkyl bromide also
produced during the reaction (usually isopropyl bromide) and
therefore results in low yields. A catalyzed version of the
Br/Mg exchange reaction would be a highly desirable process.
Recently we found that I/Zn exchange can be converted
into a catalytic reaction by the addition of [Li(acac)]
(
10 mol%, acac = acetylacetonato) to an aryl iodide and
[
4]
iPr Zn. Encouraged by these results, we have examined the
2
[
3]
effect of salt additives on the rate of Br/Mg exchange. We
chose the electron-rich and therefore unreactive 4-bromoani-
sole (1a) and treated it with iPrMgCl (1.05 equiv; 1m in THF)
in the presence of several lithium salts. A slow Br/Mg
exchange occurred in the absence of additives, leading to only
1
8% conversion after 68 h at room temperature (entry 1,
Table 1). Whereas the addition of LiBF resulted in several
4
products (entry 2), the addition of LiBr, LiI, and LiClO gave
4
minor improvements (38–40% conversion; entries 3–5). On
the other hand, the addition of LiCl (1 equiv) led to a
spectacular rate increase and 70% conversion (entry 6). The
addition of smaller amounts of LiCl resulted in lower
conversion (entries 7 and 8), whereas larger quantities did
not lead to further rate increases (entries 9 and 10). When a
[
*] Dr. A. Krasovskiy, Prof. Dr. P. Knochel
Ludwig Maximilians-Universität München
Department Chemie
Butenandtstrasse 5–13, Haus F
81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[
**] We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) for financial support. We also thank V.
Malakhov for performing some preliminary experiments as well as
Chemetall GmbH (Frankfurt), Wacker Chemie GmbH (München),
BASF AG (Ludwigshafen), and Bayer-Chemicals AG for generous
gifts of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 3333 –3336
DOI: 10.1002/anie.200454084
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3333

Communications
Table 1: Effect of the addition of lithium salts on the formation of 4-
methoxyphenylmagnesium chloride at 258C after a reaction time of 68 h
1m solution in THF).
(
[
a]
Entry
Additive
Equiv.
Conv. [%]
1
2
3
4
5
6
7
8
9
–
–
18
5
Scheme 1. Preparation of functionalized arylmagnesium reagents.
LiBF4
LiBr
LiI
1.0
1.0
1.0
1.0
1.0
0.25
0.5
1.5
2.0
1.0
40
38
38
70
22
43
73
74
iPrMgCl·LiCl, which was made by adding iPrCl to Mg
turnings and LiCl (iPrCl/Mg/LiCl = 1:1.1:1) in THF. Alter-
natively, the reagent can be prepared by addition of a solution
of iPrMgCl in THF to LiCl. This reagent was used for the
preparation of a range of aryl- and heteroarylmagnesium
derivatives (2a–p) starting from the corresponding bromides.
LiClO4
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
1
1
0
1
[
b]
+
84
After the reaction with electrophiles (E ), the expected
products (3a–p) were isolated in good to excellent yields
[
a] The conversion of the reaction was determined by GC analysis of
(Scheme 1 and Table 2).
reaction aliquots; precision Æ2%. [b] The concentration of iPrMgCl·LiCl
was 2.22m.
Thus, the previously reported reaction of 1-bromo-3-
[
6a]
fluorobenzene (1b)
with iPr Mg (1.1 equiv, RT, 3 h)
2
provided the corresponding Grignard reagent 2b with
moderate conversion, and after the subsequent reaction
with PhCHO the alcohol 3b was obtained in only 50%
yield (Scheme 2). When we conducted the reaction with
iPrMgCl·LiCl, the alcohol 3b was obtained in 85% yield.
Similarly, the reaction of 2,6-dibromopyridine (1c) with
iPrMgCl (2 equiv) was reported to afford the alcohol 3c in
more concentrated solution of iPrMgCl·LiCl (2.22m) was
used, 84% conversion was achieved (entry 11). Trapping of
[
5]
2
a with benzaldehyde furnished the benzhydryl alcohol 3a in
7
0% yield (entry 1 of Table 2). Analogous results were
obtained with other aryl- and heteroarylmagnesium deriva-
tives (Scheme 1).
Herein we describe the preparation of functionalized
arylmagnesium compounds of type 2 using the new reagent
[
6f]
42% yield. By using iPrMgCl·LiCl (1.05 equiv), we have
now obtained 3c in 89% yield (Scheme 2).
Table 2: Preparation and reaction of functionalized Grignard reagents of type 2 using iPrMgCl·LiCl.
[
a]
[b]
[a]
[b]
Entry Grignard reagent Electrophile Product
Yield Entry Grignard reagent Electrophile Product
Yield
[
d]
1
2
PhCHO
PhCHO
70
81
8
9
ClPPh2
85
PhCHO
83
[
c]
3
4
PhCOCl
PhCOCl
87
10
11
PhCHO
90
81
[
c]
c]
[c]
88
I(CH ) CO Et
2
3
2
allyl
allyl
[
[c]
5
6
7
93
90
87
12
13
14
82
88
80
bromide
bromide
allyl
bromide
[
[
c]
e]
PhCHO
PhCHO
PhCHO
[a] Y=Cl·LiCl. [b] Yield of isolated analytically pure product. [c] The Grignard reagent was transmetalated with CuCN·2LiCl before reaction with an
electrophile. [d] The reaction mixture was worked up oxidatively with aq. H O . [e] The exchange reaction was conducted in THF/DMPU (1:3).
2
2
3
334
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Moreover, when a THF/DMPU (1:3; DMPU = 1,3-dimethyl-
tetrahydro-2(1H)-pyrimidinone) mixture was used, 2-isopro-
pyl bromobenzoate could serve as a substrate. The resulting
Grignard reagent 2p (À108C, 3 h) then reacted with PhCHO
leading to lactone 3p in 80% yield (entry 14).
Only a few reports are available on the preparation of
ortho-bromophenylmagnesium halides from 1,2-dibromoben-
[
10]
zene (4). Oshima et al. have reported that lithium tribu-
tylmagnesiate (Bu MgLi) leads to the formation of benzyne
3
by means of 1,2-elimination and not to ortho-bromophenyl-
[
6c]
magnesium halide (5).
The generation of this Grignard
reagent can be achieved conveniently with iPrMgCl·LiCl.
Thus, the reaction of 4 with iPrMgCl·LiCl was complete
Scheme 2. Br/Mg exchange reactions with various magnesium
reagents.
[11]
within 2 h at À158C and led to the Grignard reagent 5.
[
9]
After transmetalation with CuCN·2 LiCl, reactions with
PhCOCl and 3-iodo-2-cyclohexen-1-one furnished the prod-
ucts 6a and 6b in yields of 84% and 86%, respectively. Also
unsymmetrical 1,2,4-tribromobenzene (7) reacted with
iPrMgCl·LiCl by means of a highly regioselective Br/Mg
The presence of an electron-withdrawing group consid-
erably increases the exchange rate, and 4-cyanophenylmag-
nesium chloride (2d) was formed within 2 h at 08C (> 95%
conversion) when iPrMgCl·LiCl was employed. In contrast,
with iPrMgCl a conversion of only 50% was reached. The
addition of PhCHO led to the alcohol 3d in 81% yield
[
11]
exchange to provide exclusively the Grignard reagent 8,
[
12]
which after reaction with pivalaldehyde gave alcohol 6c in
89% yield (Scheme 3).
(
entry 2). The position of the substituent on the aromatic ring
is not important, and both 2-cyano- and 3-cyanophenylmag-
nesium chloride 2e,f were readily prepared and benzoylated
in the presence of CuCN·2 LiCl (0.2 equiv; entries 3 and 4).
The inductive effect of the cyano group accelerates further
the formation of 2e (1 h, 08C) relative to that of 2 f (3 h, 08C).
Similar reactivity was observed for 5-bromo-3-pyridylmagne-
sium chloride (2g; prepared at À108C within 15 min, > 95%
conversion). The copper-catalyzed allylation of 2g led to
pyridine 3g in 93% yield. Other heterocyclic systems such as
3
-bromothiophene and 2-bromothiazole reacted smoothly
with iPrMgCl·LiCl at room temperature furnishing 2h and 2i,
[
7]
respectively. After reaction with PhCHO the corresponding
[
8]
alcohols 3h and 3i were obtained in yields of 87% and 90%,
respectively (Table 2, entries 6 and 7). Aryl bromides bearing
electron-donating substituents undergo the Br/Mg exchange
only slowly with iPrMgCl. The iPrMgCl·LiCl reagent was
used in an expeditive preparation of the methoxy-substituted
Scheme 3. Selective Br/Mg exchanges of polybromides.
Grignard compound 2j. Reaction with Ph PCl provided, after
oxidative workup, the phosphane oxide 3j in 85% yield
The necessity of using the stoichiometric complex
iPrMgCl·LiCl leads us to postulate that the addition of LiCl
breaks the polymeric aggregates 9 of iPrMgCl, producing the
2
(
entry 8). Similarly, sterically hindered 2,6-dichlorophenyl-
[
13]
magnesium chloride (2k) was prepared from the correspond-
ing bromide (258C, 1 h), and its reaction with PhCHO
furnished the alcohol 3k in 83% yield (entry 9). Various
unfunctionalized aromatic Grignard compounds such as 2l
and 2m can be prepared in high yields as well. Interestingly,
the copper derivative of 2m underwent a smooth cross-
coupling with I(CH ) CO Et furnishing phenanthrene 3m in
reactive complex 10 (Scheme 4). The magnesiate character
2
3
[
2
9]
8
1% yield (entry 11).
Scheme 4. Catalysis of the Br/Mg exchange reaction with LiCl.
We have also examined the formation of a Grignard
reagent bearing an ester functionality. Preliminary results
have shown that the presence of LiCl enhances the reactivity
of iPrMgCl, making the competitive addition to the ester
carbonyl group a serious side reaction. However, a tert-butyl
ester is compatible with the Br/Mg exchange reaction. The
copper-catalyzed allylation gave the desired esters 3n and 3o
in 82% and 88% yields, respectively (entries 12 and 13).
À
+
of 10 [iPrMgCl Li ] may be responsible for the enhanced
2
reactivity of this reagent. Interestingly, the magnesiate
character of the resulting organometallic complexes 11 is
similar to that of a dimeric or oligomeric magnesium reagent
prepared in the absence of LiCl (standard Grignard reagent)
but the former display higher reactivity towards electrophiles.
Angew. Chem. Int. Ed. 2004, 43, 3333 –3336
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Communications
In conclusion, we have shown that iPrMgCl·LiCl can be
V. A. Vu, Angew. Chem. 2003, 115, 4438; Angew. Chem. Int. Ed.
003, 42, 4302.
4] F. F. Kneisel, M. Dochnahl, P. Knochel, Angew. Chem. 2004, 116,
032; Angew. Chem. Int. Ed. 2004, 43, 1017.
5] Interestingly, we have noticed that the addition of LiOtBu
1 equiv, 1m solution) resulted in 92% conversion under the
2
used for the simple, high-yielding preparation of a broad
range of functionalized aryl- and heteroarylmagnesium
reagents starting from cheap and readily available aryl
[
[
1
[
14]
bromides.
All reactions proceed within a convenient
(
range of temperatures (À158C–RT) and can be extended to
the large-scale preparation of Grignard reagents. We have
demonstrated for the first time the promoter effect of LiCl in
the Br/Mg exchange reaction. Extensions of this work are
currently underway in our laboratories.
same reaction conditions. However, the reagent iPrMgCl·
LiOtBu seems to be of less general use than iPrMgCl·LiCl. See
also: a) J. J. Farkas, S. J. Stoudt, E. M. Hanawalt, A. D. Pajerski,
H. G. J. Richey, Organometallics 2004, 23, 423; b) E. M. Hana-
walt, J. J. Farkas, H. G. J. Richey, Organometallics 2004, 23, 416.
6] a) M. Abarbri, F. Dehmel, P. Knochel, Tetrahedron Lett. 1999,
[
40, 7449; for the synthesis of arylmagnesium species starting
from aryl bromides using lithium organomagnesiates for the Br/
Mg exchange reaction, see: b) K. Kitagawa, A. Inoue, H.
Shinokubo, K. Oshima, Angew. Chem. 2000, 112, 2594; Angew.
Chem. Int. Ed. 2000, 39, 2481; c) A. Inoue, K. Kitagawa, H.
Shinokubo, K. Oshima, J. Org. Chem. 2001, 66, 4333; d) A.
Inoue, K. Kitagawa, H. Shinokubo, K. Oshima, Tetrahedron
2000, 56, 9601; e) F. TrØcourt, G. Breton, V. Bonnet, F. Mongin, F.
Marsais, G. Queguiner, Tetrahedron Lett. 1999, 40, 4339; f) F.
TrØcourt, G. Breton, V. Bonnet, F. Mongin, F. Marsais, G.
QuØguiner, Tetrahedron 2000, 56, 1349.
Experimental Section
1
) Preparation of the reagent iPrMgCl·LiCl: Magnesium turnings
(
110 mmol) and anhydrous LiCl (100 mmol) were placed in an Ar-
flushed flask, and THF (50 mL) was added. A solution of iPrCl
100 mmol) in THF (50 mL) was slowly added at room temperature.
(
The reaction started within a few minutes. After the addition, the
reaction mixture was stirred for 12 h at room temperature. The gray
solution of iPrMgCl·LiCl was cannulated into another Ar-filled flask
and removed in this way from excess magnesium. iPrMgCl·LiCl was
obtained in a yield of ca. 95–98%.
[7] We treated 2-bromo-, 3-bromopyridine, and 2-bromothiophene
2
) Typical procedure (3g): A dry and argon-flushed 10-mL flask
with iPrMgCl·LiCl and obtained ca. 15–20% better yields than
[
6c]
equipped with a magnetic stirrer and a septum was charged with
iPrMgCl·LiCl (1 mL, 1.05m in THF, 1.05 mmol). The reaction mixture
was cooled to À158C, and 3,5-dibromopyridine (237 mg, 1.0 mmol)
was added in one portion. The reaction temperature was increased to
À108C, and the Br/Mg exchange was complete after 15 min (checked
by GC analysis of reaction aliquots, the conversion was more than
the analogous reactions with BuMe MgLi.
2
[8] Previous exchange conditions required both an excess of iPr Mg
2
[
6a]
and of PhCHO (> 2 equiv).
[9] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem.
1988, 53, 2390.
[10] Y. Van der Winkel, O. S. Akkerman, F. Bickelhaupt, Main
Group Met. Chem. 1988, 11, 91.
9
8%). Allyl bromide (133 mg, 1.1 mmol) was added, followed by
addition of one drop of CuCN·2 LiCl (a 1.0m solution in THF was
used, ca. 0.02 mmol, 0.02 equiv). The reaction mixture was stirred for
[11] The half-lives of magnesium reagents 5 and 8 at À108C are 24 h
and 12 h, respectively.
1
h at 08C and was then quenched with saturated aqueous NH Cl
[12] The regioselective formation of Grignard reagent 8 was proved
by quenching with water, which led to the formation of 1,4-
dibromobenzene in quantitative yield.
4
solution (2 mL). The aqueous phase was extracted with ether (3 ”
mL), dried with Na SO , and concentrated in vacuo. The crude
4
2
4
residue was purified by flash chromatography (CH Cl ) yielding 3-
[13] The
heterometallic
organomagnesium
complex
2
2
allyl-5-bromopyridine (3g; 184 mg, 93%) as a colorless oil.
RMgBr·LiBr·3THF (R = (Me Si) C) has been structurally char-
3
3
acterized: N. H. Buttrees, C. Eaborn, M. N. A. E-Khely, P. B.
Hitchcock, J. D. Smith, K. Tavakkoli, J. Chem. Soc. Dalton Trans.
1988, 381.
Received: February 23, 2004 [Z54084]
Published Online: May 26, 2004
[
14] A patent application has been filed.
Keywords: CÀC coupling · copper · cross-coupling ·
.
Grignard reaction · heterocycles
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336
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